The liver is a pivotal organ in regulating many physiological processes, such as glycogen storage, lipid metabolism, plasma protein secretion, and xenobiotic detoxification. Liver diseases, such as liver metabolic diseases and fulminant liver failure, are responsible for a huge number of deaths worldwide. Liver transplantation is currently the only curative treatment for these diseases at the end stages. In addition, primary human hepatocyte (PHH) transplantation has been recently evaluated in clinics as an alternative to organ transplantation. On the other hand, liver support devices containing functional hepatocytes have been developed in order to allow the liver to recover from acute liver failure (Carpentier et al., 2009, Gut 58, 1690-1702.). Besides the therapeutic applications, hepatocytes are widely used for disease modeling, such as hepatitis C virus infection and humanized animal models, and for drug metabolism and pharmacokinetics analysis, e.g. hepatobiliary disposition of drug candidates (Azuma, et al., 2007, Nat Biotechnol 25, 903-910; Gomez-Lechon et al., 2004, Current drug metabolism 5, 443-462; and Lazaro, et al. 2007, Am J Pathol 170, 478-489). However, the demand for liver organs and functional hepatocytes far exceeds the supply of cadaveric livers and liver tissues from living donors. Generation of surrogate hepatocytes can be used to meet these demands. Thus, there is a need for human hepatocytes or hepatocyte-like cells.
Overexpression of lineage-specific transcription factors has been used to change cell fates. Direct cell lineage conversion through reprogramming facilitates the generation of donor organ-independent cells for applications in regenerative medicine or personalized disease modeling. Whereas several studies have successfully converted mouse fibroblasts into other cell types, it is well accepted that human cells are resistant to lineage reprogramming (Nam et al. 2013, Proc Natl Acad Sci USA 110, 5588-5593; Pang et al. 2011, Nature 476, 220-223; and Qiang et al., 2011, Cell 146, 359-371). For example, trans-differentiation into neuronal cells (iN) has been demonstrated in human cells; however, the in vivo functions of human iN, especially their application in therapeutic treatment, have not yet been thoroughly characterized. A recent study managed to reprogram human fibroblasts into cells with a cardiac fate, but these cells lacked mature cardiac functions (Nam et al. 2013, Proc Natl Acad Sci USA 110, 5588-5593). Furthermore, trans-differentiated cells are proliferation arrested, which precludes them from expanding in large numbers for in vivo measurements and biomedical applications.